Photobiomodulation for Alzheimer’s disease : translating basic research to clinical application

Abstract:One of the challenges in translating new therapeutic approaches to the patient bedside lies in bridging the gap between scientists who are conducting basic laboratory research and medical practitioners who are not exposed to highly specialized journals. This review covers the literature on photobiomodulation therapy as a novel approach to prevent and treat Alzheimer’s disease, aiming to bridge that gap by gathering together the terms and technical specifications into a single concise suggestion for a treatment protocol. In light of the predicted doubling in the number of people affected by dementia and Alzheimer’s disease within the next 30 years, a treatment option which has already shown promising results in cell culture studies and animal models, and whose safety has already been proven in humans, must not be left in the dark. This review covers the mechanistic action of photobiomodulation therapy against Alzheimer’s disease at a cellular level. Safe and effective doses have been found in animal models, and the first human case studies have provided reasons to undertake large-scale clinical trials. A brief discussion of the minimally effective and maximum tolerated dose concludes this review, and provides the basis for a successful translation from bench to bedside

Mechanical Stimulation of Fibroblasts by Extracorporeal Shock Waves: Modulation of Cell Activation and Proliferation Through a Transient Proinflammatory Milieu

Extracorporeal shock waves (ESWTs) are "mechanical" waves, widely used in regenerative medicine, including soft tissue wound repair. Although already being used in the clinical practice, the mechanism of action underlying their biological activities is still not fully understood. In the present paper we tried to elucidate whether a proinflammatory effect may contribute to the regenerative potential of shock waves treatment. For this purpose, we exposed human foreskin fibroblasts (HFF1 cells) to an ESWT treatment (100 pulses using energy flux densities of 0.19 mJ/mm2 at 3 Hz), followed by cell analyses after 5 min, up to 48 h. We then evaluated cell proliferation, reactive oxygen species generation, ATP release, and cytokine production. Cells cultured in the presence of lipopolysaccharide (LPS), to induce inflammation, were used as a positive control, indicating that LPS-mediated induction of a proinflammatory pattern in HFF1 increased their proliferation. Here, we provide evidence that ESWTs affected fibroblast proliferation through the overexpression of selected cytokines involved in the establishment of a proinflammatory program, superimposable to what was observed in LPS-treated cells. The possibility that inflammatory circuits can be modulated by ESWT mechanotransduction may disclose novel hypothesis on their biological underpinning and expand the fields of their biomedical application

Pericellular Oxygen Monitoring during Low-Level Light Therapy in Cell Culture Using a Microsensor System

An electrochemical microsensor system to monitor the pericellular oxygen concentration of fibroblasts during low-level light therapy in vitro was developed. The system provides in-sight into the metabolism of the cells during and in consequence of illumination with visible red light. This approach is a unique method for real-time investigations of cellular respiration during light therapy. The presented sensor system features direct amperometric measurements by using chronoamperometric protocols for long-term stability. The oxygen measurements do not show a disturbance by light

Phototherapy with LED light modulates healing processes in an in vitro scratch-wound model using 3 different cell types

BACKGROUND: An effective way of modulating wound healing processes, including proliferation and apoptosis, is low-level light therapy. Because of several disadvantages of lasers, light-emitting diodes (LEDs) could be more feasible light sources. OBJECTIVE: To evaluate and compare the effects of blue and red light from LEDs on different cell types in an in vitro scratch-wound model. METHODS: Monolayers of C2C12 myoblasts, NIH/3T3 fibroblasts, and BICR10 keratinocytes were injured by mechanical scraping. Cells were illuminated on 5 consecutive days for 10 minutes by LED at 470 or 630 nm. Effects of light on in vitro wound healing were evaluated by analyzing time to closure, proliferation, apoptosis, and necrosis rates. RESULTS: Illumination substantially affected cell viability and cell growth. Blue light strongly decreased proliferation and augmented apoptosis in all 3 cell types and increased necrosis rates in C2C12 and NIH/3T3 cells. In contrast, red light did not alter apoptosis in either cell type but promoted proliferation in all 3 cell types with significant effects in C2C12 and NIH/3T3 cells and shortened time to closure in all 3 cell types. CONCLUSION: Light-emitting diode light illumination could be a therapeutic option and positively affect wound healing processes. By choosing appropriate wavelengths, variable effects can be achieved

Resistance of Bacteria toward 475 nm Blue Light Exposure and the Possible Role of the SOS Response

The increase in antibiotic resistance represents a major global challenge for our health systems and calls for alternative treatment options, such as antimicrobial light-based therapies. Blue light has shown promising results regarding the inactivation of a variety of microorganisms; however, most often, antimicrobial blue light (aBL) therapy is performed using wavelengths close to the UV range. Here we investigated whether inactivation was possible using blue light with a wavelength of 475 nm. Both Gram-positive and -negative bacterial strains were treated with blue light with fluences of 7.5–45 J/cm2. Interestingly, only some bacterial strains were susceptible to 475 nm blue light, which was associated with the lack of RecA, i.e., a fully functional DNA repair mechanism. We demonstrated that the insertion of the gene recA reduced the susceptibility of otherwise responsive bacterial strains, indicating a protective mechanism conveyed by the bacterial SOS response. However, mitigating this pathway via three known RecA inhibiting molecules (ZnAc, curcumin, and Fe(III)-PcTs) did not result in an increase in bactericidal action. Nonetheless, creating synergistic effects by combining a multitarget therapy, such as aBL, with an RecA targeting treatment could be a promising strategy to overcome the dilemma of antibiotic resistance in the future

Testing the effects of photobiomodulation on angiogenesis in a newly established CAM burn wound model

Abstract Burn wounds are a common challenge for medical professionals. Current burn wound models hold several limitations, including a lack of comparability due to the heterogeneity of wounds and differences in individual wound healing. Hence, there is a need for reproducible in vivo models. In this study, we established a new burn wound model using the chorioallantoic membrane assay (CAM) as a surrogate model for animal experiments. The new experimental setup was tested by investigating the effects of the auspicious biophysical therapy, photobiomodulation (PBM), on the wound healing of an induced CAM burn wound with a metal stamp. PBM has been shown to positively influence wound healing through vascular proliferative effects and the increased secretion of chemotactic substances. The easily accessible burn wounds can be treated with various therapies. The model enables the analysis of ingrowing blood vessels (angiogenesis) and diameter and area of the wounds. The established model was used to test the effects of PBM on burn wound healing. PBM promoted angiogenesis in burn wounds on day 4 (p = 0.005). Furthermore, there was a not significant trend toward a higher number of vessels for day 6 (p = 0.065) in the irradiated group. Changes in diameter (p = 0.129) and the burn area (p = 0.131) were not significant. Our results suggest that CAM can be a suitable model for studying burn wounds. The novel experimental design enables reproducible and comparable studies on burn wound treatment

Cross-modality imaging of bisphosphonate-treated murine jawbones

In this proof-of-principle study, we established and implemented a cross-modality imaging (CMI) pipeline to characterize and compare bisphosphonate (BIS)-treated jawbones of Sprague-Dawley rats after tooth extraction after physical therapies (photobiomodulation and extracorporeal shockwave therapy (PBMT and ESWT)). We showcase the feasibility of such a CMI approach and its compatibility across imaging modalities to probe the same region of interest (ROI) of the same jawbone. Jawbones were imaged in toto in 3D using micro-Computed Tomography to identify ROIs for subsequent sequential 2D analysis using well-established technologies such as Atomic Force Microscopy and Scanning Electron Microscopy, and recent imaging approaches in biomedical settings, such as micro-X-Ray Fluorescence Spectroscopy. By combining these four modalities, multiscale information on the morphology, topography, mechanical stiffness (Young's modulus), and calcium, zinc and phosphorus concentrations of the bone was collected. Based on the CMI pipeline, we characterized and compared the jawbones of a previously published clinically relevant rat model of BIS-related osteonecrosis of the jawbone (BRONJ) before and after treatment with BISs, PBMT and ESWT. While we did not find that physical therapies altered the mechanical and elemental jawbone parameters with significance (probably due to the small sample size of only up to 5 samples per group), both ESWT and PBMT reduced pore thicknesses and bone-to-enamel distances significantly compared to the controls. Although focused on BIS-treated jawbones, the established CMI platform can be beneficial in the study of bone-related diseases in general (such as osteoarthritis or -porosis) to acquire complementary hallmarks and better characterize disease status and alleviation potentials